dl-N-(4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-yl)phthalimide

ABSTRACT

This invention relates to novel derivatives of 4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine which are useful as animal growth regulants, and a process for the preparation thereof. The above-identified compounds of this invention are also useful as intermediates for the preparation of 4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thien-4-ylurea compounds.

CROSS REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 816,429, filed July 18,1977, now U.S. Pat. No. 4,134,899; which is a cont. of Ser. No. 628,716filed Nov. 4, 1975, now abandoned.

BACKGROUND OF THE INVENTION

The 4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine compounds areuseful as intermediates in the preparation of4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thien-4-ylurea compounds whichpossess animal growth regulating and herbicidal activity, and which aredescribed in detail and claimed in my co-pending Application Ser. No.532,449, filed Dec. 13, 1974, now abandoned, and Ser. No. 572,492 filedApr. 25, 1975, now abandoned, both of which are herein incorporated byreference.

SUMMARY OF THE INVENTION

This invention relates to novel4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine compounds whichare represented by formula (I) below: ##STR1## wherein R₁ representshydrogen; R₂ is selected from the group consisting of hydrogen, C₁ -C₆alkanoyl, halo-substituted C₁ -C₆ alkanoyl and ##STR2## wherein Y isselected from the group consisting of hydrogen, 3,4-dichloro, chloro,methyl, methoxy and nitro; when R₁ and R₂ are taken together with theassociated nitrogen they represent a moiety selected from the group ofcyclic imides consisting of succinimide, maleimide, phthalimide and1,2,3,6-tetrahydrophthalimide; R₃ is selected from the group consistingof oxo and hydroxyl; X is selected from the group consisting ofchlorine, bromine and iodine; n is 0, except when R₁ and R₂ are bothhydrogen; the racemic mixture and the optical isomers thereof, and whenR₃ is hydroxyl the racemic mixture and optical isomers of the cis andtrans isomers thereof, wherein the terms "cis" and "trans" refer to theconfiguration of the 7-hydroxy group with respect to the 4-amino group.

A preferred embodiment of the present invention consists of thosecompounds of formula (I) wherein R₁ is hydrogen; R₂ is selected from thegroup consisting of C₁ -C₆ alkanoyl and halo-substituted C₁ -C₆alkanoyl; when R₁ and R₂ are taken together with the associated nitrogenthey represent phthalimido; X is selected from the group consisting ofchlorine, bromine and iodine; n is 0, except when R₁ and R₂ are bothhydrogen; R₃ is selected from the group consisting of oxo and hydroxyl;and the racemic mixture, the cis and trans isomers thereof when R₃ ishydroxyl, and the optical isomers thereof.

This invention further relates to methods of preparation of theabove-described formula (I),4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine compounds,hereinbelow described and exemplified in detail.

The novel formula (I) tetrahydro-7-oxobenzo[b]thiophen-4-amine compoundsof the present invention wherein R₃ is carbonyl are prepared from thecorresponding formula (II) 4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminesby an oxidation reaction which may be graphically illustrated asfollows: ##STR3## wherein R₁ and R₂ are as defined above.

A formula (II) amine is reacted with a 2 to 8 mole equivalent,preferably with a 2 to 5 mole equivalent, of an oxidizing agent selectedfrom the group consisting of ceric ammonium nitrate, ceric sulfate,silver oxide, chromic anhydride or sodium bichromate at a temperaturebetween about 0° C. and about 100° C., preferably 20° C., to 60° C., ina solvent selected from the group consisting of aqueous solutions ofacetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane,diethylene glycol dimethyl ether, which may contain nitric acid,phosphoric acid or perchloric acid, or chromic anhydride--aceticanhyride, followed by hydrolysis. Other oxidizing agents, such aspersulfates, may also be used in the above oxidation reaction if sodesired.

The corresponding 7-hydroxy (cis and trans isomers, as defined above)analogs are prepared from the corresponding type (Ia) compounds, byreduction with equimolar or excess amounts of sodium borohydride, at atemperature range between about 0° C. and about 75° C., preferably 20°C. to 40° C., in C₁ -C₃ alcohols to afford a mixture of the cis andtrans isomers. The above reaction may be graphically illustrated asfollows: ##STR4## wherein R₁ and R₂ are as defined above.

The 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine intermediates arerepresented by formula (II) below: ##STR5## wherein R₁ representshydrogen; R₂ is selected from the group consisting of hydrogen, C₁ -C₆alkanoyl halo-substituted C₁ -C₆ alkanoyl and ##STR6## wherein Y isselected from the group consisting of hydrogen, 3,4-dichloro, chloro,methyl, methoxy and nitro; when R₁ and R₂ are taken together with theassociated nitrogen they represent a moiety selected from the group ofcyclic imides consisting of succinimido, maleimido, phthalimido and1,2,3,6-tetrahydrophthalimido; and the racemic mixtures and the opticalisomers thereof.

A 1 mole equivalent of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine isreacted with a 1 to 1.5 mole equivalent of the appropriate acidanhydride or halide (preferably the acid chloride) in the presence of ananhydrous solvent, inert to the reactants, selected from aromatichydrocarbons such as benzene, toluene and xylene; chlorinatedhydrocarbons such as methylene chloride, chloroform, ethers such astetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether and the like, or mixtures thereof at a temperature between about0° C. and about 100° C., preferably 20° C. to 50° C. for a period oftime from 1 hour to 24 hours. Acid acceptors such as trimethyl ortriethylamine, pyridine and the like or alkali metal carbonates such assodium or potassium carbonate may be utilized to good advantage in theabove reaction when the acid halides are utilized.

The novel 4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]-thiophen-4-aminecompounds of formulae Ia and Ib, obtained by the procedures hereinabovedescribed, are racemic mixtures. Should the optically active isomers offormulae Ia and Ib compounds be desired, they may be convenientlyprepared from the resolved (d or l) isomers of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine by the above describedroutes.

The compounds of this invention are useful as growth promoting agentsfor animals such as poultry, fur-bearing and farm animals and their usefor this purpose has the added advantage of improving feed conversionfor said animals. The term "feed conversion" means the ratio of unitweight of feed per unit weight of gain and "improvement in feedconversion" means increased weight gain from a given unit of feedconsumed.

A growth-promoting amount of a formula (I)4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine or an opticallyactive isomer thereof is administered to a host animal in, or with, theanimal's feed. Said compound may also be administered as a subcutaneousimplant under the skin of said animal or as a parenteral injection. Whenadministered in the feed of said animals, usually about 0.0001% to about0.08% by weight, and preferably 0.001% to 0.04% by weight of formula (I)amine, is effective for increasing growth rate and improving feedconversion. When administered as a parenteral injection or subcutaneousimplant, usually in amounts that will supply about 0.0005 mg., to about0.2 mg., preferably 0.001 mg. to 0.10 mg. per kg. of body weight per dayof the active compound, it will produce the desired improvement inweight gain and enhance food conversion.

Preparation of animal growth regulating and herbicidal urea compoundsfrom the corresponding4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine compounds of thepresent invention may be accomplished by a number of alternate routes,as set forth in the following paragraphs.

A formula I amine, except when R₁ and R₂ are both hydrogen, ishydrolyzed in dilute mineral acid and the resulting4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-amine of formula (III)is reacted with an equimolar or excess (5% to 50%) amount of sodium orpotassium cyanate at a temperature in the range of 0° C. to 100° C.,preferably 0° C. to 70° C., in the presence of a solvent selected fromthe group consisting of water, C₁ -C₃ alcohols, tetrahydrofuran,dioxane, ethylene glycol dimethyl ether, acetone, methyl ethyl ketone orthe like or mixtures thereof in the pH range of 5 to 7, and preferably apH 6. The above reaction may be graphically illustrated as follows:##STR7## wherein R₃ represents oxo or hydroxy. The formula IV compoundsobtained are the racemic mixtures and the cis and trans isomers thereof,wherein R₃ is hydroxyl.

To obtain a formula IV substituted urea of formula III amine is reactedwith an isocyanate of the formula: R-NCO under conditions similar tothose described above yield a formula IV urea of the structure: ##STR8##wherein R₃ is as defined above and R represents a substituent such asalkyl, alkoxy, benzyl, phenyl, substituted phenyl and the like selectedto enhance the biological activity and/or to impart suitable physicalproperties to said urea.

An amine of formula (III) where R₃ is oxo, may be reacted with phosgene,preferably under anhydrous conditions, under a blanket of inert gas suchas nitrogen. The reaction is initially carried out at a temperaturebetween about 0° C. to about 40° C., preferably 10° C. to 20° C., andthen heated to between about 50° C. and about 100° C., preferably from60° C. to 80° C. to yield the isocyanate of formula (V): ##STR9##wherein R₃ is oxo. This reaction is usually conducted in the presence ofan organic solvent such as benzene, toluene or xylene. The thus obtainedisocyanate of formula (V) is then reacted with an equimolar or excess(5% to 50%) amount of an amine of the formula ##STR10## to yield aformula IV urea of the structure: ##STR11## wherein R₃ is as definedabove; R₄ and R₅ represent substituents such as alkyl, alkoxy, benzyl,aryl groups and the like selected to favorably enhance the biologicalactivity and/or physical properties of said urea. For the preparation ofcompounds of formula IV, wherein R₃ is hydroxyl, the corresponding oxocompounds are conveniently reduced with sodium borohydride in C₁ -C₃alcohols.

The thus obtained animal growth promoting urea compounds of formula IVare the racemic mixtures of the cis and trans isomers when R₃ ishydroxyl; unless, of course, the reaction sequence leading to said ureasis started with the resolved (d or l) formula (III) amines.

In practice, the 4,5,6,7-tetrahydro-7-oxo(oxy)benzo[b]thien-4-ylureacompounds of formula (IV) are administered to a host animal orally orparenterally as previously described.

The present invention is further illustrated by the examples set forthbelow.

Specific Disclosure EXAMPLE 1 Preparation ofN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine

In 725 ml of 50% aqueous acetic acid, 39 g ofN-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred while 473g of ceric ammonium nitrate is added over 15 minutes at about 25° C.After 15 minutes of additional stirring, sodium chloride is added andthe mixture is extracted 3 times with dichloromethane (500, 500 and 250ml). The combined extract is washed with brine and then with water. Thewater is extracted with 100 ml of dichloromethane and combined with themain dichloromethane solution. Evaporation of the dichloromethane invacuo gives a sticky gum, which when triturated with 100 ml of etheraffords 28.4 g. of the title compound, m.p. 96° C. to 106° C.

EXAMPLE 2 Preparation ofN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine

A suspension of 22.4 g of ceric sulfate in 50% aqueous acetic acid isstirred overnight at room temperature and 2 g ofN-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added. After 6hours, the mixture is filtered, and the filter cake is washed with 50%aqueous acetic acid. The work-up procedure of Example 1 is then followedwith the filtrate to give 1.1 g of the title compound, m.p. 102 to 114°C.

EXAMPLE 3 Preparation ofN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine

In 6 ml of acetic anhydride, 1 g ofN-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred and 1.52g of chromium trioxide is 6.8 ml of acetic anhydride is added at 15° C.to 28° C. over 45 minutes. After 2 hours the mixture is poured intoice-water, and after an overnight period the aqueous mixture issaturated with sodium chloride and extracted with 2×100 ml ofdichloromethane. The combined extract is washed with brine andevaporated to dryness to afford 0.84 g of a brown oil. Trituration ofthe oil with ether affords 0.5 g of the title compound, m.p. 109° C. to112° C.

Oxidation of N-formyl-4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine withchromic acid/acetic acid, ceric ammonium nitrate/potassiumpermanganate/aqueous acetic acid, potassium peroxydisulfate/silvernitrate/aqueous acetic acid, t-butyl chromate/carbon tetrachloride,chromium trioxide/pyridine/dichloromethane, sodium dichromate/aceticanhydride/acetic acid, sodium dichromate/acetic acid, chromiumtrioxide/aqueous acetic acid, and chromium trioxide/aceticanhydride/acetic acid, respectively, also affords the title compound.

EXAMPLE 4 Preparation ofN-Acetyl-4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine

A solution of 2.15 g ofN-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 12 ml of aceticacid is stirred and 3.04 g of chromium trioxide in 13.6 ml of aceticanhydride is added in 15 minutes at 10° C. to 15° C. After an hour at20° C., 20 ml of water is added and the mixture is allowed to standovernight. Additional water (50 ml) is added, the mixture is saturatedwith sodium chloride and extracted with trichloromethane (100, 150 and50 ml volumes). The combined extract is washed with brine and then withwater. The water wash is extracted with trichloromethane and the extractis combined with the main trichloromethane extract. Evaporation of theextract affords a yellow-green residue, which after trituration withether gives 1.32 g of the title compound, m.p. 160° C. to 164° C.

EXAMPLE 5 Preparation ofN-trichloroacetyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine

Into 2 equivalents of trichloroacetic anhydride, 1 equivalent of4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added to afford the amide,which is collected and dried. TheN-trichloroacetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine melts at80° C. to 86° C. This material is then oxidized in the manner describedin Example 1 to afford the title product, m.p. 167° C. to 171° C.

EXAMPLE 6 Preparation ofN-chloroacetyl-4,5,6,7-tetrahydrobenzo[b]-thiophen-4-amine

A mixture of 7.59 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-aminehydrochloride is stirred in 60 ml of dry tetrahydrofuran and 10.1 g oftriethylamine in 20 ml of dry tetrahydrofuran is added. After stirringunder a nitrogen atmosphere for 15 minutes, 3.5 ml or 5.25 g ofchloroacetyl chloride in 30 ml of dry tetrahydrofuran is added dropwise,while the temperature is maintained at 30° C. to 40° C. After an hour ofstirring, the mixture is filtered, the filter cake is washed withtetrahydrofuran, and the filtrate is evaporated to dryness. The residueis then triturated with water and the title compound, m.p. 115° C. to119° C., is collected and washed with water and hexane.

EXAMPLE 7 to 27

The following compounds, exemplified by structure B, are prepared byfollowing the method of Example 1. The corresponding starting materials,exemplified by structure A, are prepared by the methods of eitherExample 5 or Example 6.

    ______________________________________                                         ##STR12##                                                                                        ##STR13##                                                 Example            R                                                          ______________________________________                                         7                 CCl.sub.3                                                  8                  CH.sub.2 Cl                                                9                  CHCl.sub.2                                                 10                 CF.sub.3                                                   11                 CH.sub.2 CH.sub.3                                          12                 CH(CH.sub.3).sub.2                                         13                 CH.sub.2C(CH.sub.3).sub.3                                  14                 (CH.sub.2).sub.4 CH.sub.3                                  15                 C.sub.6 H.sub.5                                            16                 4-chlorophenyl                                             17                 2-chlorophenyl                                             18                 3-chlorophenyl                                             19                 4-nitrophenyl                                              20                 3-nitrophenyl                                              21                 2-nitrophenyl                                              22                 4-methoxyphenyl                                            23                 2-methoxylphenyl                                           24                 4-methoxylphenyl                                           25                 2-methylphenyl                                             26                 3-methylphenyl                                             27                 4-methylphenyl                                             28                 3,4-dichlorophenyl                                         ______________________________________                                    

EXAMPLE 29 Preparation ofN-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)-phthalimide

In 50 ml of toluene, 5 g of4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamine, 4.84 g of phthalicanhydride, and 0.5 ml of triethylamine are heated at reflux toazoetropically remove water. After the distillation of water iscompleted, the mixture is cooled, the crystals are collected and washedwith ether to affordN-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)phthalimide, m.p. 166° C. to167.5° C. Oxidation of this compound by the method of Example 1 affordsthe title compound, m.p. 163° C. to 166° C.

Acid hydrolysis hydrochloric acid/ethanol of this imide affords4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride.

Similarly, use of maleic anhydride, cis-1,2,3,6-tetrahydrophthalicanhydride, and succinic anhydride in place of phthalic anhydride affordsN-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)maleimide,-cis-1,2,3,6-tetrahydrophthalimide and -succinimide, respectively.

EXAMPLE 30 Preparation of4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine and its hydrochloridesalt

A 2 g sample ofN-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is heated atreflux with 10 ml of 95% ethanol and 10 ml of 2 N hydrochloric acid for5 hours. The solution is evaporated to dryness and the residuetriturated with acetone to afford the title compound, m.p. 224° C. to225° C. dec. Substitution of hydrochloric acid with hydrobromic acid orhydroiodic acid affords the corresponding salts of the amine.Neutralization of the hydrochloride salt with 10% aqueous sodiumhydroxide and extracting the aqueous mixture with ethylene dichloride,followed by evaporation of ethylene dichloride affords7-oxobenzo[b]thiophen-4-amine.

In the same manner, acid hydrolyses of compounds of structure B(Examples 4 to 28) also afford the above title amine hydrochloride whilealkaline hydrolyses (1 equivalent of potassium hydroxide/ethanol innitrogen atmosphere) of the same ketoamides afford the title amine.

EXAMPLE 31 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea

An aqueous solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-aminehydrochloride (1.01 g/5 ml water) is treated with 0.81 g of potassiumcyanate in 2 ml of water at pH 6-7 to afford the title compound, whichis collected and washed with water to afford 0.93 g, m.p. 241° C. to242° C. dec.

EXAMPLE 32 1-Methyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea

In 50 ml of dichloromethane, 8.1 g of4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is stirred under anitrogen atmosphere and 2.9 g of methyl cyanate in 50 ml ofdichloromethane is added dropwise at below 30° C. After stirring for anhour, the title compound is collected, m.p. 212° C. to 215° C.

EXAMPLE 33 Preparation of (-)N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine

In 275 ml of toluene, 52.45 g of (+)4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is stirred under a nitrogenatmosphere and 40 ml of 97% formic acid is added in 15 minutes at about35° C. The mixture is then heated to reflux and water is removed byazeotroping. After water no longer is distilled over, the mixture iscooled and the white titel compound is collected and washed withtoluene. The title compound melts at 132.5° C. to 134° C., with [α]_(D)²⁴ =-119.7° C., C=4.01 in acetic acid.

Similarly (-) N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine isprepared by using acetic anhydride instead of formic acid.

EXAMPLE 34 Preparation (-)N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine

The ceric ammonium nitrate oxidation of (-)N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine by the method ofExample 1 affords the title compound, m.p. 130° C. to 136° C., [α]_(D)²⁴ =-144.4° C., C=0.514 in acetic acid.

Similarly, (-) N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine isoxidized to afford (-)N-acetyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine.

EXAMPLE 35 Preparation of (-)4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylurea

An appropriate amount of (-)N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]-thiophen-4-amine is hydrolyzedby the method of Example 30 and coverted to the title compound by themethod of Example 31. The product melts at 247° C. to 249.5° C. dec,with [α]_(D) ²⁴ =-97.2° C., C=0.141 in methanol.

EXAMPLE 36 Preparation of4,5,6,7-Tetrahydro-7-hydroxy-benzo[b]thien-4-ylacetamide

Twenty-seven g (0.129 M) of4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylacetamide is dissolved inabsolute ethanol (270 ml) and treated with sodium borohydride (4.9 g,0.129 M). The mixture is stirred at room temperature overnight, water(250 ml) is added and stirring continued for 2 hours. The bulk of theethanol is evaporated and the precipitated solid is filtered off, washedtwice with water (total 50 ml) and air dried to afford the titlecompound (13.73 g, 50.4% yield) as an off white solid, m.p. 175° C. to179° C. dec.

The analytical specimen is obtained by recrystallization fromacetone/hexane and melts at 170° C. to 178° C. dec. The mother liquorson standing furnish a second crop of title compound (10.83 g, 39.7%yield), m.p. 102° C. to 145° C. dec.

EXAMPLE 37 Mouse Growth Regulant Tests

CFI female mice from Carworth Farm are received when they are 6 weeksolds. They are housed 10 to a cage in air-conditioned rooms (72° F. to76° F.) with automatically controlled lights, 14 hours on and 10 hoursoff. The basal diet used in these studies is Purina Laboratory Chow (seedescription below), which is supplied ad libtium. Water is also allowedad libitum.

Thirteen days after arrival, the mice are weighed in groups of 10 andassigned at random to the different treatments. The concentration of thedifferent compounds in the diet is indicated in the following Table.Twelve days later the mice are weighed again and the experimentterminated. At least 3 cages (30 mice) of untreated controls areincluded in each test. Test data are provided in Table I below whereindata are reported as percent weight gain over controls. The following isa description of the diet to which the growth promoting compounds areadded.

    ______________________________________                                        Diet                                                                          ______________________________________                                        Guaranteed Analysis                                                           Crude protein not less than                                                                            23.0%                                                Crude fat not less than  4.5%                                                 Crude fiber not more than                                                                              6.0%                                                 Ash not more than        9.0%                                                 ______________________________________                                        Ingredients                                                                   Meat and bone meal, dried skimmed milk, wheat germ                            meal, fish meal, animal liver meal, dried beet                                pulp, ground extruded corn, ground oat groats,                                soybean meal, dehydrated alfalfa meal, cane molasses,                         animal fat preserved with BHA, vitamin B.sub.12 supplement,                   calcium pantothenate, choline chloride, folic acid,                           riboflavin supplement, brewers' dried yeast, thiamin,                         niacin, vitamin A supplement, D activated plant                               sterol, vitamin E supplement, calcium carbonate, di-                          calcium phosphate, iodized salt, ferric ammonium                              citrate, iron oxide, manganous oxide, cobalt                                  carbonate, copper oxide, zinc oxide.                                          ______________________________________                                    

    ______________________________________                                        Effectiveness of 4,5,6,7-Tetrahydro-7-oxo(oxy)benzo[b]thiophen-4-             amines As Animal Growth Promoting Agents Reported as Percent                  Weight Over Controls Using Mice as the Test Animal                             ##STR14##                                                                                                          %                                                                             Weight                                  Rate                                  Gain                                    ppm in                                Over                                    Diet  R.sub.1         R.sub.2  R.sub.3                                                                              Controls                                ______________________________________                                        400   H               CH.sub.3 CO                                                                            oxo    38.5                                    400   H               CH.sub.3 CO                                                                            hydroxyl                                                                             18.5                                    400                                                                                  ##STR15##               oxo     9.5                                    ______________________________________                                    

EXAMPLE 38

By the method of Example 37, the animal growth promoting activity oftetrahydro-7-oxobenzo[b]thien-4-ylureas derived from the compounds ofthe present invention is evaluated. The data obtained is provided inTable II.

    ______________________________________                                         ##STR16##                                                                    Rate ppm                         % Weight Gain                                in Diet  R.sub.4 R.sub.5  R.sub.3                                                                              Over Control                                 ______________________________________                                        400      H       H        oxo    134                                           25      H       H        oxo    135                                                 (levorotary)                                                           ______________________________________                                    

EXAMPLE 39 Preparation of 4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylurea

A sample of 18.95 g ofN-acetyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is heated toreflux temperature with 6N hydrochloric acid for 4 hours. The mixture iscooled, filtered through glass wool to remove tars and the tars arewashed twice with 75 ml of water. The combined washes and filtrate iswashed with dichloromethane and then evaporated to dryness in vacuo. Theresidue is dissolved in 75 ml of water and a solution of 12.5 g ofpotassium cyanate in 35 ml of water is added rapidly. After stirringovernight, the product is collected by filtration and washed with waterand then with methanol. This affords 7.7 g of the title compound, m.p.231° C. to 234° C. dec.

I claim:
 1. The compunddl-N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)phthalimide.